The somatomedins/insulin-like growth factors (Sm/IGF) are a group of biologically active peptides that may be important in fetal development. To better define the roles of these peptides, it is important to define the receptors that mediate their biologic actions. Interpretation of in vitro studies is complicated by the fact that there is significant cross-reactivity between the Sm/IGFs and type I and II Sm/IGF receptors as well as the insulin receptor. We have shown that a highly specific antibody (aIR3) to the type I Sm/IGF receptor, that blocks Sm-C binding and action, also inhibits the mitogenic action of insulin-like growth factor II (IGF-II) in human foreskin fibroblasts. This suggests that this action of IGF-II is mediated through the type I receptor. On the other hand, investigation of the specificity of aIR3 and its effect on IGF-II binding to human placental membranes has led to the discovery of an immunologically distinct binding site for IGF-II. We cannot yet discriminate between the possibility that this represents a 'type III' receptor with a structure similar to the type I or whether there is a discrete binding site for IGF-II on the type I receptor. We plan to further characterize the putative 'type III' receptor with affinity labeling techniques and to purify the type I receptor to better assess its interaction with IGF-II. We plan to extend these observations to other actions of the Sm/IGFs including amino acid uptake and to study the effect of age by repeating these studies in fibroblasts from different aged donors. By examining the interaction of IGF-II with these tissues at the molecular level and by extending our observations of its actions in vitro, we hope to better understand the role of this growth factor in the human fetus.